Susumu Tonegawa’s research while affiliated with Massachusetts Institute of Technology and other places

The extinction of conditioned fear responses is crucial for adaptive behavior, and its impairment is a hallmark of anxiety disorders such as posttraumatic stress disorder. Fear extinction takes place when animals form a new memory that suppresses the original fear memory. In the case of context-dependent fear memory, the new memory is formed within the reward-responding posterior subset of basolateral amygdala (BLA) that is genetically marked by Ppp1r1b ⁺ neurons. These memory engram cells suppress the activity of the original fear-responding Rspo2 ⁺ engram cells present in the anterior BLA, hence fear extinction. However, the neurological nature of the teaching signal that instructs the formation of fear extinction memory in the Ppp1r1b ⁺ neurons is unknown. Here, we demonstrate that ventral tegmental area (VTA) dopaminergic signaling drives fear extinction in distinct BLA neuronal populations. We show that BLA fear and extinction neuronal populations receive topographically divergent inputs from VTA dopaminergic neurons via differentially expressed dopamine receptors. Fiber photometry recordings of dopaminergic activity in the BLA reveal that dopamine (DA) activity is time-locked to freezing cessation in BLA fear extinction neurons, but not BLA fear neurons. Furthermore, this dopaminergic activity in BLA fear extinction neurons correlates with extinction learning. Finally, using projection-specific optogenetic manipulation, we find that activation of the VTA DA projections to BLA reward and fear neurons accelerated or impaired fear extinction, respectively. Together, this work demonstrates that dopaminergic activity bidirectionally controls fear extinction by distinct patterns of activity at BLA fear and extinction neurons.

Benign uterine leiomyoma (U.LMA) and malignant uterine leiomyosarcoma (U.LMS), which are both uterine mesenchymal tumors, are distinguished by the number of cells with mitotic activity. However, uterine mesenchymal tumors contain tumor cells with various cell morphologies; therefore, making a diagnosis, including differentiation between benign tumors and malignant tumors, is difficult. For example, round ligament leiomyomas are uterine leiomyomas with a very rare placental lobed tissue morphology that can be misdiagnosed as a malignant uterine leiomyosarcoma because of its rarity and characteristic appearance on gross examination. Similar to the detection of a suspicious malignant mass during magnetic resonance imaging (MRI) examination by medical staff, healthcare professionals must understand the characteristic appearance of round ligament leiomyomas. Clinicians and pathologists must understand the oncologic features of round ligament leiomyomas to prevent misdiagnosis of malignancy and consequent overtreatment.

Anterior cingulate cortex mediates the flexible updating of an animal’s choice responses upon rule changes in the environment. However, how anterior cingulate cortex entrains motor cortex to reorganize rule representations and generate required motor outputs remains unclear. Here, we demonstrate that chemogenetic silencing of the terminal projections of cingulate cortical neurons in secondary motor cortex in the rat disrupts choice performance in trials immediately following rule switches, suggesting that these inputs are necessary to update rule representations for choice decisions stored in the motor cortex. Indeed, the silencing of cingulate cortex decreases rule selectivity of secondary motor cortical neurons. Furthermore, optogenetic silencing of cingulate cortical neurons that is temporally targeted to error trials immediately after rule switches exacerbates errors in the following trials. These results suggest that cingulate cortex monitors behavioral errors and updates rule representations in motor cortex, revealing a critical role for cingulate-motor circuits in adaptive choice behaviors. The anterior cingulate cortex allows an animal to update its behaviour when the environment changes. In this work, the authors identify a pathway from cingulate to secondary motor cortex, critical for updating motor rules following behavioural errors.

Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos+ brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage. Where memories are located in our brains is not well understood. In this paper, the authors demonstrate that memories are spread out throughout multiple brain regions.

Anterior cingulate cortex mediates the flexible updating of an animal's choice responses upon rule changes in the environment. However, how anterior cingulate cortex entrains motor cortex to reorganize rule representations and generate required motor outputs remains unclear. Here, we demonstrate that chemogenetic silencing of the projection terminals of cingulate cortical neurons in secondary motor cortex disrupted sequential choice performance in trials immediately following rule switches, suggesting that these inputs are necessary to update rule representations for choice decisions stored in the motor cortex. Indeed, the silencing of cingulate cortex decreased rule selectivity of secondary motor cortical neurons. Furthermore, optogenetic silencing of cingulate cortical neurons that was temporally targeted to error trials immediately after rule switches exacerbated errors in following trials. These results suggest that cingulate cortex monitors behavioral errors and update rule representations in motor cortex, revealing a critical role for cingulate-motor circuits in adaptive choice behaviors.